Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)

ABSTRACT

The invention concerns orthoester and orthocarbonate polymers having a repeating mer comprising a hydrocarbon radical and a symmetrical dioxycarbon unit of the general formula: ##STR1## WHEREIN R 1  is a multivalent hydrocarbon radical, R 2  and R 3  are hydrocarbon radicals with at least one of R 2  or R 3  bonded to the dioxycarbon through an oxygen linkage, and which polymers are synthesized by reacting a polyol with an orthoester or orthocarbonate. The polymers are useful for making articles of manufacture, including devices and coatings for delivering beneficial agents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to polymers. More particularly, theinvention pertains to novel and useful polymers comprising acarbon-oxygen backbone having a dioxycarbon moiety with a plurality oforganic groups pendant from the dioxycarbon. The polymers arerepresented by the following general formula: ##STR2## WHEREIN R₁ is adi, tri or tetravalent alkylene, alkenylene, alkyleneoxy, cycloalkylene,cycloalkylene substituted with an alkyl, alkoxy or alkenyl,cycloalkenylene, cycloalkenylene substituted with an alkyl, alkoxy oralkenyl, arylene, or a arylene substituted with an alkyl, alkoxy oralkenyl, R₂ and R₃ are alkyl, alkenyl, alkoxy, alkenyloxy, alkylene,alkenylene, alkyleneoxy, alkenyleneoxy, alkylenedioxy, alkenylenedioxy,aryloxy, aralkyleneoxy, aralkenyleneoxy, aralkylenedioxy,aralkenylenedioxy, oxa, or OR₁ O with R₁ defined as above; and wherein,(a) R₁ is divalent when R₂ and R₃ are alkyl, alkenyl, alkoxy, oralkenyloxy, with at least one of R₂ or R₃ an alkoxy or alkenyloxy; (b)R₁ is divalent when R₂ and R₃ are intramolecularly covalently bonded toeach other and to the same dioxycarbon atom to form a heterocyclic ringor a heterocyclic ring substituted with an alkyl, alkoxy or alkenyl whenR₂ is an alkyleneoxy or alkenyleneoxy and R₃ is an alkyleneoxy,alkenyleneoxy or alkylene; (c) R₁ is divalent when R₂ and R₃ areintramolecularly covalently bonded to each other and to the same dioxycarbon atom to form a fused polycyclic ring or a fused polycyclic ringsubstituted with an alkyl, alkoxy or alkenyl when R₂ is an oxa,alkyleneoxy or alkenyleneoxy and R₃ is aryloxy, aralkyleneoxy,aralkenyleneoxy or aralkylene; (d) R₁ is divalent when R₂ or R₃ is anOR₁ O bridge between polymer backbones bonded through their dioxycarbonmoieties, and the other R₂ or R₃ is an alkyl, alkenyl, alkyloxy, oralkenyloxy; (e) R₁ is tri or tetravelent when R₂ and R₃ are covalentlybonded to each other and to the same dioxycarbon atom to form aheterocyclic ring or a heterocyclic ring substituted with an alkyl,alkoxy or alkenyl when R₂ is an alkyleneoxy or alkenyleneoxy and R₃ isan alkyleneoxy, alkenyleneoxy or alkylene; (f) R₁ is tri or tetravalentwhen R₂ and R₃ are covalently bonded to each other and to the same dioxycarbon atom to form a fused polycyclic ring or fused polycyclic ringsubstituted with an alkyl, alkoxy or alkenyl when R₂ is an oxa,alkyleneoxy or alkenyleneoxy and R₃ is aryloxy, aralkyleneoxy,aralkenyleneoxy or aralkylene.

The polymers provided by the invention include homopolymers, copolymersof the random and block types formed by reacting monomers or mixtures ofpreformed homopolymers and/or copolymers, branched polymers andcross-linked polymers. The invention also makes available to the artthermoplastic linear polymers when R₁ is divalent, R₂ and R₃ aresubstituted with a noncross-linking group or are bondedintramolecularly; thermosetting cross-linked polymers when R₁ isdivalent and R₂ or R₃ is intermolecularly bonded between differentpolymeric backbones; and, thermosetting cross-linked polymers when R₁ istri or tetravalent and R₂ and R₃ are substituted with noncross-linkinggroups, or bonded intramolecularly.

2. Description of the Prior Art

The reaction of orthoesters with glycols leading to non-polymeric andother diverse products is known to the art in the references such asInd. J. Appl. Chem., Vol. 28, No. 2, pages 53 to 58, 1965 whereinMehrota, et al obtained monoethoxy-monoglycolate andtriglycoxy-bisorthoformate by reacting orthoformate with hexamethyleneglycol in molar ratios of one to one, and two to three to yield lowmolecular weight compounds. Similarly, Crank, et al in Aust. J. Chem.,Vol. 17, pages 1392 to 1394, 1964, disclosed the reaction of triols withorthoesters including ethyl orthoformate with butane 1,2,4-triol,pentane-1,2,5-triol and pentane-1,3,5-triol to form monomeric bicycliccompounds. During the preparation of the bicyclic orthoesters byreacting ethyl orthoformate with triols, Crank, et al found thatcompounds produced from starting materials having a 1,2-diol structurealso contained compounds having ethylene linkages. In a subsequentpaper, Crank, et al Aust. J. Chem., Vol. 17, pages 1934 to 1938, 1964,developed this reaction into a synthetic procedure for the conversion of1,2-diols into olefins. Later, DeWolfe in Carboxylic Ortho AcidDerivatives, 1970, published by Academic Press, Inc., New York, notedthat carboxylic orthoesters are more reactive toward acid hydrolysisthan almost any other class of compounds, and this high hydrolyticreactivity complicates their synthesis and storage. DeWolfe reportedthat the conversion of diols to cyclic orthoesters includingalkoxydioxolane or alkoxydioxane, followed by acid hydrolysis, providesa method for monoacylating diols. More recently, Bailey reported inPolym. Prepr. Amer. Chem. Soc. DIv. Polym. Chem., Vol. 13, No. 1, pages281 to 286, 1972, that the polymerization of spiro orthoesters atambient and elevated temperatures led to polyesters and polycarbonatesof the structures [--CH₂ CH₂ CH₂ COOCH₂ CH₂ O-- ]_(n) and [--OCH₂OCOOCH₂ CH₂ CH₂ --]_(n).

SUMMARY OF THE INVENTION

The invention concerns a new class of polymers comprising a polymericbackbone having a repeating unit comprising hydrocarbon radicals and asymmetrical dioxycarbon unit with a multiplicity of organic groupsbonded thereto. The polymers prepared by the invention have a controlleddegree of hydrophobicity with a corresponding controlled degree oferosion in an aqueous or like environment to innocuous products. Thepolymers can be fabricated by conventional techniques into assortedarticles of manufacture having various shapes. The polymers can be usedfor making devices and coatings for releasing a beneficial agent, as thepolymers erode at a controlled rate, and thus can be used as carriersfor drugs for releasing drug at a controlled rate to a drug receptor,especially where bioerosion is desired.

DETAILED DESCRIPTION OF THE INVENTION

The phrase hydrocarbon radical appearing above and as used elsewhere inthe specification, includes, for the purpose of this invention, theterms embraced by R₁, R₂ and R₃ as defined below.

The term alkylene used in this specification for R₁ denotes a straightor branched chain divalent, trivalent or tetravalent alkylene radical of2 to 10 carbon atoms inclusive such as 1,2-ethylene; 1,3-propylene;1,2-propylene; 1,4-butylene; 1,5-pentylene; 1,6-hexylene;1,2,5-hexylene; 1,3,6-hexylene; 1,7-heptylene; 2-methyl-1,7-heptylene;1,8-octylene; 1,10-decylene; 2-propyl-1,6-hexylene;1,1-dimethyl-1,6-hexylene; and the like. These alkylene chains arederived from the corresponding glycols.

The term alkenylene used for R₁ denotes an unsaturated straight orbranched chain multivalent radical having 2 to 10 carbon atoms such as1,4-but-2-enylene; 1,6-hex-3-enylene; 1,7-hept-3-enylene;1,8-oct-3-enylene; 1,9-non-3-enylene; 4-propyl-(1,6-hex-3-enylene);5-methoxy-(1,6-hex-3-enylene); 2-propenyl-(1,6-hex-3-enylene); and thelike.

The term cycloalkylene as used for R₁ includes monocyclic, lowercycloalkylene radicals of 3 to 7 carbons such as cyclopropylene;cyclobutylene; cyclopentylene; cyclohexylene and cycloheptylene.Similarly, the phrase cycloalkylene substituted with an alkyl of 1 to 7carbons, an alkoxy of 1 to 7 carbons, or an alkenyl of 2 to 7 carbons,includes substituted cycloalkylenes such as 2-methyl-1,3-cyclopropylene;2-methyl-1,4-cyclopentylene; 2-methyl-1,6-cyclohexylene;2-ethoxy-2,3-cyclopropylene; 5-butoxy-1,4-cyclopentylene;2-methoxy-1,4-cyclohexylene; 2-propenyl-1,5-cyclopentylene;2-isobutenyl-1,6-cyclohexylene; and the like.

Exemplary R₁ cycloalkenylene and R₁ cycloalkenylene substituted with analkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, or an alkenyl of 2to 7 carbons, include monocyclic alkenylenes having from 4 to 7 carbonsas ring members, such as 1,4-cyclopent-2-enylene;1,5-cyclopent-3-enylene; 1,6-cyclohex-2-enylene; 1,6-cyclohex-2-enylene;and the substituted rings such as 5-methyl-(1,4-cyclopent-2-enylene);6-ethyl-(1,4-cyclohex-2-enylene); 6-ethoxy-(1,5-cyclohex-2-enylene);2-propyl-(1,5-cyclohex-3-enylene); 2-methoxy-(1,4-cyclohex-2-enylene);2-methoxy-(1,4-cyclohept-2-enylene), and the like.

The expressions R₁ arylene and R₁ arylene substituted with an alkyl of 1to 7 carbons, an alkenyl of 2 to 7 carbons, or an alkoxy of 1 to 7carbons, include the benzenoid groups such as phenylene, phenylalkyleneand phenylalkenylene. Typical groups are 1,4-phenylene;1,4-phenyldimethylene; 1,4-phenyldiethylene;2,ethyl-1,4-phenyldimethylene; 2-methyl-1,4-phenyldimethylene;2-methoxy-(1,4-phenyldimethylene); 2-propyl-(1,4-phenyldiethylene); andthe like.

The term alkyl appearing herein for R₂ and R₃, and as a substituent onthe aryl, cycloalkyl and heterocyclic group, embraces straight andbranched chain alkyl radicals of 1 to 7 carbon atoms such as methyl;ethyl; n-propyl; n-butyl; n-amyl; n-hexyl; n-heptyl and the variouspositional isomers thereof such as isopropyl; t-butyl; sec-butyl;isoamyl; isohexyl; t-heptyl and the like.

Exemplary alkenyls as used for R₂ and R₃, and as a substituent on thearyl, cycloalkyl and heterocyclic group, include the straight andbranched chain lower alkenyl groups of 2 to 7 carbons such as1-propenyl; 2-propenyl or allyl; 1-butenyl; 2-butenyl; 1-pentenyl;2-ethenyl; and the corresponding positional isomers such as1-isobutenyl; 2-isobutenyl; 2-sec-butenyl; 2-methyl-1-butenyl;2-methyl-2-pentenyl; 2,3-dimethyl-3-hexenyl; and the like.

The term alkoxy as used for R₂ and R₃, and as a substituent on the aryl,cycloalkyl and heterocyclic group, include the straight and branchedchain lower alkoxy groups and the positional isomers thereof having 1 to7 carbon atoms inclusive, for example, methoxy; ethoxy; propoxy; butoxy;n-pentoxy; n-hexoxy; isopropoxy; 2-butoxy; isobutoxy; 3-pentoxy; and thelike.

The term alkenyloxy as used for R₂ and R₃ embraces the straight andbranched chain lower alkenyloxy groups and the positional isomersthereof having 2 to 7 carbon atoms, for example, ethenoxy; propenoxy;butenoxy; pentenoxy; hexenoxy; isopropenoxy; isobutenoxy; sec-butenoxy;2-methyl-1-butenoxy; 2-methyl-2-butenoxy; 2,3-dimethyl-3-butenoxy; andthe like.

The term alkyleneoxy appearing in the general formula comprehends, forR₁, R₂ and R₃, straight and branched chain alkyleneoxy radicals of theformula --OR₄ -- wherein R₄ is an an alkylene of 2 to 6 carbons, forexample, 1,3-propyleneoxy; 1,4-butyleneoxy; 1,5-pentyleneoxy;1,6-hexyleneoxy; 2,2-dimethyl-1,4-butyleneoxy; and the like. Similarly,the term alkenyleneoxy comprehends, for R₂ and R₃, radicals of thegeneral formula --OR₅ -- wherein R₅ is an alkenylene of 3 to 6 carbons,such as prop-1-enyleneoxy; 1,4-but-1-enyleneoxy; 1,4-but-2-enyleneoxy;1,5-pent-1-enyleneoxy; 1,6-hex-1-enyleneoxy; and the like.

The expressions alkylenedioxy and alkenyldioxy include the straight andbranched chain radicals of the formula --OR₄ O-- wherein R₄ is analkylene of 2 to 6 carbons and of the formula --OR₅ O-- wherein R₅ is analkenylene of 3 to 6 carbons, such as for alkylenedioxy propylenedioxy;butylenedioxy; pentylenedioxy; hexylenedioxy; and heptylenedioxy; andfor alkenylenedioxy prop-1-enylenedioxy; 1,4-but-1-enylenedioxy;1,4-but-2-enylenedioxy; 1,5-pent-1-enylenedioxy; 1,6-hex-1-enylenedioxy;and 1,7-hep-1-enylenedioxy. The phrase heterocyclic ring of 5 to 8carbons for R₂ and R₃, defines the ring formed when R₂ or R₃ is a bond,alkylene or alkenylene, and at least one of R₂ or R₃ is an alkyleneoxy,alkenyleneoxy, alkylenedioxy or alkenylenedioxy with the terms asdefined above.

The terms alkylene and alkenylene used when R₂ and R₃ are independentlytaken together to form a ring in cooperation with the carbon of thecarbon-oxygen polymeric backbone, include an alkylene of 2 to 6 carbonsand an alkenylene of 3 to 6 carbons, such as the alkylenes 1,2-ethylene,1,3-propylene, 1,4-butylene, 1,5-pentylene, and 1,6-hexylene, and thealkenylenes 1,3-prop-1-enylene, 1,4-but-1-enylene, 1,4-but-2-enylene,1,5-pent-1-enylene, 1,6-hex-2-enylene, and 1,7-hept-2-enylene.

The terms aryloxy, aralkyleneoxy, aralkenyleneoxy, aralkylenedioxy andaralkenylenedioxy used for R₂ and R₃ include a radical of 8 to 12carbons wherein aryloxy is ar--o--, alkyleneoxy is --OR₄ --,alkenyleneoxy is --OR₅ --, alkylenedioxy is --OR₄ O--, alkenylenedioxyis --OR₅ O--, with R₄ an alkylene and R₅ an alkenylene as defined above,and ar is phenyl. The phrase fused polycyclic ring of 8 to 12 carbons asused herein, defines a substituent in which a heterocyclic and an arylring have two atoms in common, for example, benzfuryl; benzpyranyl;4,5-benz-1,3-dioxepanyl; 5,6-benz-1,3-dioxepanyl;4,5-benz-1,3-dioxolanyl; 4,5-benz-1,3-dioxyolanyl;4,5-benz-1,3-dioxocanyl; 5,6-benz-1,3-dioxocanyl;6,7-benz-1,3-dioxocanyl; 7,8-benz-1,3-dioxocanyl; andbenz-1,3-dioxoanyl.

The term mer as used herein for polymers, copolymers and terpolymersdenotes the member unit or the monomeric unit of the polymer. Forexample, in a homopolymer, the mer units are the same. In a copolymer,the mer unis are different and that can be ordered in the polymer chainin a random fashion when the original units are copolymerized in acommon reaction vessel, or they can be ordered in block fashion when thepolymers are combined after an initial homopolymerization of each of thedifferent monomeric units. A terpolymer is similar to a copolymer withan added third mer unit.

The novel polymers of the invention are synthesized by intimatelycontacting and reacting at least one starting polyol with at least onestarting compound of the general formula ##STR3## to yield thecorresponding polymer.

Exemplary polyols suitable as reactants include diols, triols and thelike that can enter into the polymerization reaction without adverselyeffecting it or the polymeric product. The polyols are known to the artin reported synthesis and they are commercially available. Generally,they include α,ω -aliphatic diols, triols and the like of the straightor branched chain type. Representative polyols are alkane polyols havinga terminal hydroxyl group at the terminus of an alkylene chain of theformula ##STR4## wherein R₇ is an alkylene chain of 3 to 12 carbon atomsand y is 0 to 6. Typical diols, named as the glycols include1,5-pentylene glycols; 1,6-hexylene glycol; 1,7-heptylene glycol;1,9-nonylene glycol; 2,3-dimethyl-1,6-hexylene glycol;3,6-diethyl-1,9-nonylene glycol; 1,12-dodecamethylene glycol; and thelike.

Polyols containing more than 2 reactive hydroxyl radicals suitable foruse herein include polyhydroxyl compounds such as1,2,3,4,5,6-hexanehexol; 1,2,3-propanetriol; 1,2,5-pentanetriol;1,3,5-pentanetriol; 1,2,4-butanetriol; 2-methyl-1,2,3-propanetriol;2-methyl-2(hydroxymethyl)1,2-propanediol; 1,4,7-heptanetriol;1,5,10-decanetriol; 1,5,12-dodecanetriol; and the like.

Other polyols suitable for synthesizing the polymers include polyglycolscontaining a repeating glycol monoether moiety --OCH₂ (CH₂)_(p) OHwherein p is 1 to 5, and the polyglycols are diglycols, triglycols,tetraglycols, and the like. Typical polyglycols include diethyleneglycol, triethylene glycol, tetraethylene glycol, bis(4-hydroxybutyl)ether, bis(3-hydroxypropyl) ether, and the like.

Additional polyols that can be used in accordance with the invention arepolyhydroxyl compounds having 2 or more reactive hydroxyl groups such aspentaerythritol; dipentaerythritol; β-methylglycerol; 1,4-cyclohexanedicarbinol in the cis, trans isomeric configuration or mixtures thereof;2,2,4,4-tetramethyl cyclobutane 1,3-diol; adonitol; mannitol;2,5-dipropyl-1,4-phenyldipropanol; 1,3-cyclopropanol;2-propenyl-1,4-cyclohexane dipropanol; trimethylol propane; sorbitol;penacol; 2-methyl-1,4-cyclohexane dicarbinol;3-isopropoxy-1,4-cyclohexane dipropanol; 2-ethenyl-1,3-cyclopentanedicarbinol; 1,4-phenyldicarbinol; 2-propyl-1,4-phenyldiethanol;3-butoxy-1,4-phenyldibutanol; and the like. The preparation of the abovepolyols is known to the art in Acta Pharm. Jugaslav, Vol. 2 pages 134 to139, 1952; Ann., Vol. 594, pages 76 to 88, 1955; J. Am. Chem. Soc., Vol.71, pages 3618 to 3621, 1949; ibid., Vol. 74, pages 2674 to 2675, 1952;Chem. Abst., Vol. 42, pages 8774 to 8775, 1948; ibid., Vol 43, pages 571to 573 and 6652, 1949; ibid., Vol. 44, pages 2554 and 7231, 1950; ibid.,Vol. 46, page 9585, 1952; ibid., Vol. 47, page 7575, 1953; ibid., Vol.48, page 106, 1954; ibid., Vol. 49, pages 6098 to 6099, 1955;Encyclopedia of Chemical Technology, Kirk-Othmer, Vol. 10, pages 638 to678, 1966, published by Interscience Publishers, New York.

Exemplary starting monomers of the formula ##STR5## include when R₂ andR₃ are as previously described and R₆ is the same or different straightor branched chain lower alkyl radical of 1 to 7 carbons the estersdescribed below, with the presently preferred alkyl radicals comprisingmethyl and ethyl. The monomers can be simple or mixed ortho esters.These include trimethylorthoformate, tri-n-butyl orthoformate, tri-hexylorthoformate, dibutylmonoethyl orthoformate,sec-butyldiethylorthoformate, methyldiethyl orthoformate,ethyldi-isopropyl orthoformate, di-isopropylbutyl formate, and the like.Additional orthoesters include ethylorthoacetate, methylorthoacetate,ethylorthopropionate, methylorthopropionate, sec-butylorthopropionate,propylorthopropionate, and the like ortho esters.

Typical alkenyl orthoester monomers include compounds of the formula R₂R₃ C(OR₆)₂ wherein R₃ is alkenyl as previously described, embracingmonomers such as dimethylethenyl orthoformate, diethylpropenylorthoformate, di-isopropylethenyl orthoformate, dimethylisobutenylorthoformate, and the like. Also, orthocarbonates including simple ormixed tetraalkyl orthocarbonates such as dipropyl-dimethylorthocarbonate, diethyl-dimethyl orthocarbonate, tetraethylorthocrbonate, tetramethyl orthocarbonate, trimethyl-sec-butylorthocarbonate, and the like.

Additional monomers are those of the formula R₂ R₃ C(OR₆)₂ wherein R₂,R₃ and R₆ are alkyl include compounds such as 2,2-dimethoxypropane;2,2-diethoxypropane; 2,2-dipropoxypropane; 2,2-dimethoxybutane;2,2-dihexyloxypentane; 2-methyloxy-2-ethoxypropane; and the like.Representative monomers when R₆ is alkyl and one of R₂ or R₃ is alkenylinclude the compounds 3,3-dimethyloxy-1-butylene;3,3-diethyloxy-1-butylene; 3,3-diethoxy-1-hexylene and the like. Also,when R₂ and R₃ are alkenyloxy, monomers such as1,2-dimethoxy-1,1-diethenoxyethane; 1,2-diethoxy-1,1-diethenoxyethane;diethenoxyethane; 1,3-diethoxy-2,2-dipropenoxypentane;1,4-diethoxy-3,3-dibutenoxybutane, and the like.

Monomers embraced by the formula ##STR6## wherein R₂, R₃ and R₆ are aspreviously defined, and R₂ and R₃ when taken together form a saturatedor unsaturated cyclic or heterocyclic ring includes monomers such as2,2-dialkoxy-1,3-dioxolane; 2,2-dialkoxy-1,3-dioxanes;2,2-dialkoxy-1,3-dioxepane; 2,2-dialkoxy-1,3-dioxocane;2,2-dialkoxy-1,3-dioxonane; 2,2-dialkenyloxy-1,3-dioxolane;2,2-dialkenyl-1,3-dioxane; 2,2-dialkenyloxy-1,3-dioxepane;2,2-dialkoxytetrahydrofuran; 2,2-dialkoxypyran; 2,2-dialkoxy-1-ocane;2,2-dialkoxy-1-oxepane; fused rings such as2,2-dialkoxy-benz-1,3-dioxolane; 2,2-dialkoxy-benz-1,3-dioxanes;2,2-dialkoxy-benz-1,3-dioxepane; 2,2-dialkoxy-benz-1,3-dioxocane;2,2-dialkoxy-benz-1,3-dioxonane; and the like.

Representative of the above monomers substituted with reactive groupsinclude 2,2,5-trimethoxy-3,4-dihydrofuran;2,2-diethoxy-4,5-benz-1,3-dioxolane;2,2-dimethoxy-4,5-benz-1,3-dioxolane;2,2-sec-butyl-4,5-benz-1,3-dioxolane; 2,2-dimethoxyl,3-dioxane,2,2-diethoxy-1,3-dioxane; 2,2-dipropoxy-1,3-dioxane;2,2-dimethoxy-4,5-benz-6-keto-1,3-dioxane;2,2-diethoxy-4,5-benz-6-keto-1,3-dioxane;2,2-diethoxy-3,4-benz-tetrahydrofuran,2,2-dimethoxy-4-phenyl-5,6-dihydro-1,3-dioxane;2,2-dimethoxy-4-phenyl-6-methyl-5,6-dihydro-1,3-dioxane;2,2-dimethoxy-3,3-dimethyl-5-phenyl-4,5-dihydrofuran;2,2-diethoxy-3-methyl-5-phenyldihydrofuran;2,2-dimethoxy-3-propyl-5-phenyl-dihydrofuran;2,2-dimethoxy-3-phenyl-5,6-benz-3,4-dihydro-1,3-dioxane;2,2-diethenyloxy-5-methyltetrahydrofuran;2,2-diethenyloxy-1,3-dioxolane; 2,2-dipropoxy-1-oxapane;2,2-dibutoxy-1-ocane; 2,2-diethenyloxy-1-oxapane;2-ethoxy-2-propoxy-1-ocane; 2-isopropoxy-2-ethoxy-1,3-dioxonane;2,2-diethoxy-5,5-dimethylpyran; 2,2-diethoxy-5-methyl-tetrahydrofuran;and the like.

Other esters of the formula ##STR7## wherein R₆ is as defined and R₂ andR₃ form a cycloalkyl ring include 1,1-dialkoxy cyclopropane;1,1-dialkoxycyclobutane; 1,1-dialkoxycyclopentane;1,1-dialkoxycyclohexane; and like monomers such as1,1-dimethoxycyclobutane; 1,1-diethoxycyclopentane;1,1-diethoxy-3-dimetholcyclopentane; 1,1-diethoxy-3-proplycyclohexane;and the like.

The above ortho esters and like ortho esters can be prepared accordingto the following preparations. The Pinner synthesis as described inBer., Vol. 16, pages 352 to 363, 1883; and ibid., pages 1644 to 1663,1883, wherein an appropriate nitrite is reacted with an equivalentamount of dry hydrogen halide and an equivalent amount of alcohol toform an iminoester hydrohalide. This is then alcoholized with an excessof alcohol to form the orthoester. The Pinner reaction is set forth asfollows: RCN+R₁ OH+HX→RC(NH₂ X)OR₁ +R₁ OH RC(OR₁)₃ +NH₄ X

Orthoesters suitable for the purpose of the invention also can beprepared by the Mkhitaryan reaction as described in Gen. Chem.,U.S.S.R., Vol. 8, pages 1361 to 1367, 1938, wherein an alkoxy group of areadily available orthoester such as triethyl orthoacetate or formateare replaced by a higher boiling alcohol or polyol according to thegeneral reaction: RC(OC₂ H₅)₃ +3R'OH→RC(OR')₃ +3C₂ H₅ OH. Theorthoesters may also be prepared by alcoholysis of trihaloalkyl groupsas set forth in J. Am. Chem. Soc., Vol. 54 pages 2964 to 2966, 1932; asindicated by the following reaction: RCX₃ +3NaOR₁ →RC(OR₁)₃ +3NaX.

The preparation of orthoesters including those of the ring type, isknown to the art with ample description of the various methods ofpreparation as found in U.S. Pat. Nos. 2,409,699; 2,867,667; 3,323,925;and 3,546,188; and in British Pat. Nos. 853,405; and 1,099,559. Also, asfound in Synthetic Organic Chemistry, Chapter 16, pages 542 to 545,1953, published by John Wiley and Sons; in The Chemistry of theAliphatic Orthoesters, Chapter 2, pages 11 to 43, 1943; ReinholdPublishing Corp.; in Encyclopedia of Chemical Technology, Kirk Othmer,Vol. 8, pages 365 to 383, 1965, Interscience Publishers, New York;Recueil Trav. Chem. Pays, Bes, Vol. 88, pages 897 to 904, 1909; J. Am.Chem. Soc., Vol. 64, pages 1825 to 1927, 1942; Ind. Eng. Chem. Prod.Res. Develop., Vol. 10, No. 4, pages 425 to 428, 1971; J. Am. Chem.Soc., Vol. 71, pages 40 to 46, 1949; Ann. Chem., Vol. 675, page 142,1964; Angew. Chem., Vol. 69, page 371, 1957; J. Am. Chem. Soc., Vol. 76,pages 5736 to 5739, 1954; ibid., Vol. 77, pages 5601 to 5606, 1955;Chem. Ber., Vol. 89, page 2060, 1956; Aust. J Chem., Vol. 17, pages 1385to 1398, 1964; Gazz. Chem. Ital., Vol. 96, page 1164, 1966; Chem.Commun., page 13, 1967; and Carboxylic Ortho Acid Derivatives, Chapter1, pages 1 to 133, 1970, published by Academic Press, New York. Theortho esters can also be prepared by conventional techniques includingalcoholysis, condensation, elimination and reduction reactions asdescribed in Organic Functional Group Preparations, by Sandler and Karo,Vol. II, Chapter 2, pages 41 to 68, 1971, published by Academic Press.

The novel polymers of the invention can be synthesized by intimatelycontacting and reacting a polyol monomer with an orthoester ororthocarbonate monomer to yield the corresponding polymer. Generally,the polymerization reaction is carried out by reacting stoichiometricamounts or an excess of polyol to yield the polymer. That is, the amountof each reactive monomer can be from about 1 to 10 moles of polyol to 1mole of orthoester or orthocarbonate monomer.

The polymerization of the monomers is carried out in a reaction vesselequipped with a stirrer and vacuum attachment with continuous mixing ofthe monomers in the presence of a catalyst. The polymerization comprisesan initial transesterification reaction followed by a polycondensationreaction with the complete polymerization performed at a temperature of60° C to 220° C and over a reaction time of 1 hour to 96 hours. Thetransesterification step of the reaction consists in mixing the monomersand catalyst, and while continuously stirring the monomers, thetemperature was gradually raised to 180° C. The transesterificationreaction for most monomers, occurs at 75° C to 180° C over a 1 to 12hour reaction period and at normal atmospheric pressure with continuousdistillation of the alcohol. The polycondensation reaction is commencedby reducing the pressure to 0.10 to 0.0001 mm of mercury and, whilemaintaining the elevated temperature and reduced pressure, carrying outthe polycondensation by continuously mixing and reacting the reactantsfor 12 to 96 hours to yield the polymer.

The polymer is recovered under anhydrous conditions from the reactionvessel by conventional isolation and recovery techniques. For example,the polymer is recovered while hot by extruding or pouring, or thepolymer is isolated after cooling, by dissolving it in a dry organicsolvent such as benzene, carbon tetrachloride, methylene chloride,dioxane, toluene or xylene, followed by the addition of an organicliquid in which the polymer is insoluble or has limited solubility toprecipitate the polymer. Organic liquids for this latter purpose includeether, hexane, pentane, petroleum ether, hexane heptane mixtures, andthe like. The polymer is isolated by filtering and drying underanhydrous conditions. Other methods for recovering the polymer includelyophilizing from a solvent.

Representative catalysts for performing the polymerization reaction areLewis acids such as boron trifluoride, boron trichloride, borontrichloride etherate, boron trifluoride etherate, stannic oxychloride,phosphorous oxychloride, zinc chloride, phosphorous pentachloride,calcium acetate, antimonous oxide mixture, antimony pentachloride,antimony pentafluoride, stannous octoate, stannic chloride, diethylzinc, n-butyl lithium, and mixtures thereof. The catalysts also includeBronsted catalysts such as p-toluene sulfonic acid, polyphosphoric acid,cross-linked polystyrene sulfonic acid, acidic silica gel, and mixturesthereof. Other catalysts include neutral or basic catalysts such astetrabutyl titanate, and titanium sodium hydrogen hexabutoxide. Theamount of catalyst used is about one part catalyst to about 500 parts ofthe ester monomer. Smaller or larger amounts can also be used, such as0.005% to about 2.0% based on the weight of the starting monomer.

The polymerization optionally can be carried out in the presence of aninert organic solvent that does not adversely affect the reaction, orthe reaction can proceed in the absence of added solvent. In the latterreaction one of the reactants, for example, the polyol initially servesas the solvent. As polymerization proceeds, solvent by-product isremoved from the reaction by conventional distillation, azeotropicdistillation, or by distillation under vacuum. Suitable azeotropicsolvents include toluene, benzene, m-xylene, cumene, pyridine, andn-heptane.

The following examples are set forth as representative methodsillustrative of the spirit of the present invention. These examples arenot to be construed so as to limit the scope of the invention as theseand other functionally equivalent means will be readily apparent tothose skilled in the subject art.

EXAMPLE 1

To 45 grams (0.312 moles) of anhydrous trans-1,4-cyclohexane dicarbinoland 0.05 grams of polyphosphoric acid in a commercially availablepolymerization reactor was added with constant stirring under an inertnitrogen environment and normal atmospheric pressure 50 grams (0.312moles) of anhydrous 2,2-diethoxytetrahydrofuran. Next, the mixture washeated to 110°-115° C and held at this temperature for 11/2 to 2 hours,with slow distillation of any liquid formed. Then, while maintaining thetemperature, the pressure was gradually reduced to 0.01 mm of mercuryand at this reduced pressure the temperature was slowly increased to180° C. The reaction was continued at this temperature for 24 hours. Thepolymer was isolated by extruding it from the reactor. The polymer hadthe following structure, where n is the degree of polymerization from 10to 1000, and the infrared spectrum as seen in FIG. 1. ##STR8##

EXAMPLES 2 - 4

Following the procedure of Example 1, but replacingtrans-1,4-cyclohexane dicarbinol and 2,2-diethoxytetrahydrofuran with:

trans-2-methyl-1,4-cyclohexane diethanol and2,2-dimethoxytetrahydrofuran;

trans-2-methyl-1,4-cyclohexane dipropanol and2,2-dimethoxytetrahydrofuran; and,

trans-2-ethyl-1,4-cyclohexane dicarbinol and2,2-diethoxy-5-methyl-3,4-dihydrofuran; the following polymers areformed: ##STR9##

EXAMPLE 5

Repeating the procedure of Example 1, but replacing2,2-diethoxytetrahydrofuran with a 2,2-di-alkoxytetrahydrofuran selectedfrom the group of 2,2-dimethoxytetrahydrofuran;2,2-dipropoxytetrahydrofuran; 2,2-dibutoxytetrahydrofuran; thecorresponding polymer of the following formula is obtained. ##STR10##

EXAMPLE 6

To 45 grams (0.312 mole) of dry cis-trans-1,4-cyclohexane dicarbinol and0.05 grams of p-toluene sulfonic acid was added with constant agitation,50.5 grams (0.312 mole) of 2,2-dimethoxy-5-methyl-1,3-dioxolane and thepolymerization reaction of Example 1 repeated to yield the polymer shownbelow. ##STR11##

EXAMPLE 7

To a mixture of 44.2 grams (0.375 mole) of freshly distilled1,6-hexanediol and 0.05 gram of polyphosphoric acid under a nitrogenblanket at atmospheric pressure was added with constant stirring 60.0grams (0.375 mole) of 2,2-diethoxytetrahydrofuran and the mixture heatedto 110° to 115° C. The mixture was held at this temperature for 1.5 to 2hours as ethanol slowly distilled from the reactor. Then, the pressurewas reduced to 0.01 mm Hg over a 2 hour period and at this vacuum thetemperature was elevated to 180° C over a similar 2 hour period. Thereaction was allowed to continue for 24 hours to yield the polymer withthe structure shown below (n is 10 to 1000). The infrared spectrum forthe polymer is seen in accompanying FIG. 2. ##STR12##

EXAMPLE 8

To 54.7 grams (0.312 mole) of 1,10-decane diol and 0.05 grams ofpolyphosphoric acid in a reactor vessel under a nitrogen environment andat atmospheric pressure was added with constant stirring 50.0 grams(0.312 mole) of 2,2-diethoxytetrahydrofuran. Next, the mixture washeated to 110° to 115° C and held at this temperature for 1.5 to 2 hoursas ethanol gently distilled from the reactor. Then, while maintainingthis temperature, the pressure was reduced to 0.01 mm of mercury and atthis reduced pressure the temperature was raised to 180° C. Thepolycondensation was continued for 24 hours to yield the polymer withthe structure shown below and with a degree of polymerization of 10 to1000. ##STR13##

EXAMPLE 9

Repeating the procedure of Example 8, but replacing 1,10-decane diol and2,2-diethoxytetrahydrofuran with stoichiometric amounts of the monomers1,4,7-heptanetriol and 2,2-diethoxy-1,3-dioxolane, the following polymeris obtained. ##STR14##

EXAMPLE 10

To 7.38 grams (0.625 mole) of 1,6-hexane diol and 0.10 grams ofpolyphosphoric acid was added 100.0 grams (0.625 mole) of2,2-diethoxytetrahydrofuran and 81.0 gram (0.562 mole) oftrans-cyclohexane dicarbinol, and the polymerization carried outaccording to the procedure of Example 1. The random copolymer obtainedhad a molecular weight, (Mw) of 11,500 and the following structure,wherein n is 10 to 1000. ##STR15##

EXAMPLE 11

The procedure of Example 1 and 7 was repeated in this example, and allconditions and reagents were as described except that in this example,the reactive diol was 1,7-heptane diol instead of 1,6-hexane diol. Therandom copolymer recovered had the indicated structure, wherein n is 10to 1000. ##STR16##

EXAMPLE 12

1.71 grams (2.85 mmole) of glycolaldehyde and 4.66 grams (2.90 mmole) of2,2-diethoxytetrahydrofuran were mixed and continuously stirred under aninert gas at 120° C and normal atmospheric pressure for 30 minutes toinsure mixing of the reactive monomers. Next, trace amounts of Lewisacid catalyst was added and the pressure gradually decreased to 60 mmHg. The ethanol was distilled into a side-arm borosilicate flask. Then,the pressure was reduced to 0.1 mm Hg and the reaction continued for 3hours. Finally, the temperature was raised to 180° C, the pressurereduced to 0.06 mm Hg and the polycondensation continued for 20 hours.The polymer formed is soluble in tetrahydrofuran and has the followingstructure: ##STR17##

EXAMPLE 13

To 66.3 grams (0.625 moles) of diethylene glycol and 0.1 gram ofpolyphosphoric acid in a stainless steel polymerization reactor wasadded 100 gram (0.625 moles) of 2,2-diethoxytetrahydrofuran withconstant stirring under an argon backflow, and the reactants heated to110°-115° C for 2 hours with distillation of ethanol formed during thetransesterification step. Then, while holding the temperature constant,the pressure was reduced from atmospheric to 0.01 mm Hg and held therewith the temperature slowly elevated to 180° C. The polycondensation wasallowed to proceed for 24 hours under these conditions to yield thepolymer shown below. ##STR18##

EXAMPLES 14 - 18

The procedure of Example 13 was followed in these examples, with all thereaction conditions as described, except the monomers of the previousexample were replaced with stoichiometrically equivalent amounts of thefollowing monomers:

(a) 1,5-pentylene glycol and 2,2-dipropoxy-4-methyltetrahydrofuran;

(b) 2,3-dimethyl-1,6-hexylene glycol and2,2-dipropoxy-5-methyltetrahydrofuran;

(c) 3,6-dimethyl-1,9-nonylene glycol and 2,2-dipropoxy-5-ethyltetrahydrofuran;

(d) 1,6-hexylene glycol and 2,2-diethoxy-3,4-dihydrofuran; and

(e) 1,6-hexylene glycol and 2,2-diethoxy-5-methyl-3,4-dihydrofuran; toyield the following polymers: ##STR19##

EXAMPLES 19 - 21

The procedure employed in Example 13 was followed in these examples withall the reaction conditions as previously described. The startingmonomers listed below were used in equivalent amounts for those ofExample 13. The monomers are:

2,2,4,4-tetramethylcyclobutane 1,3-diol and 2,2-diethoxytetrahydrofuran;

triethylene glycol and 2,2-diethoxy-5,5-dimethyltetrahydrofuran;

triethylene glycol and 2,2-diethoxy-5-methoxytetrahydrofuran; to yieldthe following polymers, wherein y is 3 and n is 10 to 1000. ##STR20##

EXAMPLE 22

To a mixture of polyol monomers consisting of 41.58 grams (0.284 mole)of trans-cyclohexane dicarbinol; 7.53 grams (0.071 mole) of theoxyalkylene glycol; diethylene glycol and 0.057 gram of polyphosphoricacid was added 56.7 gram (0.355 mole) of diethoxytetrahydrofuran underthe inert gas argon and the mixture heated to 115° C for 2 hours withcontinuous distillation of the liquid organic by-product. Then, whilekeeping the temperature constant, the pressure was reduced to 0.01 mm ofHg and at this reduced pressure the temperature was raised to 180° C.The reaction was continued at this temperature and vacuum for 24 hours.The random copolymer was isolated by extruding it from the reactor andit had the following configuration where n is 10 to 1000. ##STR21##

EXAMPLE 23

The procedure used for preparing the copolymer in Example 22, wasrepeated in this polymerization; all conditions were as described. Themonomers used in this example were 2,2-diethoxytetrahydrofuran,1,6-hexanediol and a mixture of cis-trans-1,4-cyclohexane dicarbinol.The structure of the copolymer obtained is as follows: ##STR22##

EXAMPLE 24

To 2.3 grams (0.0195 mole) of 1,6-hexanediol was added with stirring12.5 grams (0.078 mole) of 2,2-diethoxytetrahydrofuran and the mixtureheated to 150° C for 3 hours under nitrogen to form an end-capped diolwhich was collected at 146°-154° C, and 0.1 mm Hg. The end-capped diolhas the following structure: ##STR23##

Next, 3 grams (0.00087 moles) of the freshly prepared end-capped diolwas heated with an additional 1 equivalent of 1,6-hexanediol in apolymerization flask under nitrogen at 100°-120° C for one hour, withcondensation first removed by simple distillation and then bydistillation under reduced pressure (0.2 mm Hg) at 120° C, to yield apolymer of the following structure: ##STR24##

EXAMPLE 25

To 14.77 grams (0.125 mole) of 1,6-hexanediol was added 20.0 g (0.125mole) of 2,2-diethoxytetrahydrofuran and 20 mg of p-toluene sulfonicacid and the monomers reacted according to the procedure of Example 1 toyield poly(2,2-dioxohexamethylene tetrahydrofuran) having a molecularweight of 15,700. Separately, 45 grams (0.312 moles) ofcis-trans-1,4-cyclohexane dicarbinol and 0.05 grams of p-toluenesulfonic acid was added to 50 grams (0.312 moles) of2,2-diethoxytetrahydrofuran and the monomer reacted according to theprocedure of Example 1 to yieldpoly-(2,2-dioxo-cis,trans-cyclohexanedimethylene tetrahydrofuran) havinga molecular weight of 24,700. Then, 9.5 grams (0.051 mole) of thepoly(2,2-dioxohexymethylene tetrahydrofuran) was copolymerized with10.76 grams (0.051 mole) ofpoly(2,2-dioxo-cis,trans-cyclohexanedimethylene tetrahydrofuran) for 43hours at 180° C under 0.01 mm Hg in the presence of trace amounts ofacid catalyst to yield the block copolymer of the following formula,when the ratio of m to n is 1 to 1, and the degree of polymerization is10 to 1000: ##STR25##

EXAMPLE 26

13.26 grams (0.125 mole) of diethylene glycol was added to 20.0 grams(0.125 mole) of 2,2-diethoxytetrahydrofuran, and the monomers reacted inthe presence of a Lewis acid catalyst for 42 hours according to thegeneral procedure in Examples 11 and 12 to yield a polymer having amolecular weight of about 20,000. Separately, 50.0 grams (0.312 mole) oftrans-1,4-cyclohexane dicarbinol and 50 grams (0.312 mole) of2,2-diethoxytetrahydrofuran were reacted according to the procedure ofExample 1 to yield another polymer. Next, 5.94 grams (0.0341 mole) ofthe former polymer was mixed with 14.5 grams (0.0682 mole) of the latterpolymer and the reaction carried out at 180° C, and under 0.01 mm Hg forfour days to yield a block copolymer. The copolymer was dissolved inbenzene and lyophilized for later use. The structure of the copolymer isas follows: ##STR26##

EXAMPLES 27 - 30

The procedure of Example 1 was followed in this example, with all thereaction conditions identical to those as previously set forth; however,the monomer of Example 1 was replaced with the monomers set forth below:

(a) 2,2-dimethoxy-4,5-benz-1,3-dioxolane (61.5 gram, 0.3 mole) and1,6-hexamethylene diol (39.5 grams, 0.3 mole);

(b) 2,2-dimethoxy-4,5-benz-1,3-dioxoane (66.3 grams, 0.3 mole) and3-hexenylene-1,6-diol (48.3 grams, 0.3 mole);

(c) 2,2-diethoxy-4,5-benz-1,3-dioxolane (106 grams, 0.5 mole) anddiethylene glycol (41 grams, 0.5mole); and,

(d) 2,2-diethoxy-1,methylcyclohexyl ortho carbonate (73 grams, 0.3 mole)and 1,6-hexamethylene diol (39.3 grams, 0.3 mole); to yield thefollowing polymers: ##STR27##

EXAMPLE 31

136 grams (1.0 mole) of anhydrous 1,3,3,5-pentane tetraol and 0.075grams of titanium sodium hydrogen hexabutoxide are added to 162 grams(1.0 mole) of anhydrous 2,2-diethoxy-1,3-dioxolane and the reactantsstirred to produce a homogenous mixture. Next, the mixture is heated to115° C for 2 hours with distillation of the continuous forming liquidinto a side-arm collector. Then, with the temperature constant, thepressure is reduced to 0.01 mm Hg and at this pressure the temperatureis raised to 180° C, with the reaction continued at the raisedtemperature for 48 hours to yield the polymer below. ##STR28##

EXAMPLES 32 - 35

Following the procedure of Example 31, with all reaction conditions asdescribed, except that the polyols and heterocyclic ortho ester of theexample are replaced with the following monomeric pairs:

(a) 1,3,5-pentane triol, 120 grams, and asymetrical2-propoxy-2-ethoxy5-methyl-1,3-dioxolane, 178 grams;

(b) 1,10-decanediol, 174 grams, and 2,2-diethoxy-5-methyl-1,3-dioxane,180 grams;

(c) 1,10-decanediol, 174 grams, and 2,2-diethoxy-1,3-dioxepane, 178grams; and,

(d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1,3-dioxocane, 218grams; to yield the following polymers: ##STR29##

EXAMPLES 36 - 39

Repeating the procedure of Example 31, the transesterification andpolycondensation steps are repeated with the following reactivemonomers:

(a) 1,6-hexanediol, 122 grams, and 2,2-diethoxytetrahydropyran, 174grams;

(b) 1,6-hexanediol, 122 grams, and2,2-diethoxy-5,5-dimethyl-tetrahydropyran, 202 grams;

(c) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1-oxepane, 188 grams;and,

(d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-Δ³ -oxyepin, 172 grams;to yield the following polymers where n is 10 to 1000: ##STR30##

EXAMPLES 40 - 44

In Table 1 below, copolymers prepared according to the spirit of theinvention are structurally illustrated. In the table, "No." refers tothe polymer; "Ratio" is the ratio of "m" and "n"; "Type" is "B" forblock copolymer and "R" is for random copolymer and the degree ofpolymerization is 10 to 1000.

                                      Table 1                                     __________________________________________________________________________    No.                                                                              Ratio                                                                             Type                                                                             Polymer                                                             __________________________________________________________________________    40 1:1 B                                                                                 ##STR31##                                                          41 1:2 B                                                                                 ##STR32##                                                          42 4:1 R                                                                                 ##STR33##                                                          43 4:1 R                                                                                 ##STR34##                                                          44 4:1 R                                                                                 ##STR35##                                                          __________________________________________________________________________

EXAMPLE 45

In the present example, polymers having the general formula set forthbelow are prepared, wherein R₁ is as previously defined, b is 2 to 6,and n is to 10 to 1000: ##STR36##

To 50 grams (0.312 mole) of diethoxytetrahydrofuran was added 45 grams(0.312 mole) of trans-cyclohexanedicarbinol and 0.05 grams ofpolyphosphoric acid and the monomers introduced into a polymerizationreactor under a positive nitrogen flow to form a reaction mixture. Next,the mixture was stirred at 60 rpm at 110°-115° C and at atmosphericpressure for 1.5 hours with slow distillation of ethanol. Then, thepressure was reduced to 0.01 mm Hg over a 2 hour period. When the highvacuum was attained, the temperature was increased to 180° C over aperiod of about 2 hours, and the polymerization was terminated after 24hours of reaction time with the polymer extruded from the reactor into aTeflon® coated beaker. The polymer had a Mn, number average molecularweight of 1.63×10⁴, a Mw weight, average molecular weight of 7.70×10⁴, aDP, degree of polymerization, of 77 and a Mw/Mn equal to 4.69. Thepolymer has the following structure: ##STR37##

EXAMPLES 46 - 48

In Table 2, polymers prepared according to Example 45 from the monomers2,2-diethoxytetrahydropyran, 2,2-diethoxy-1-oxepane,2,2-diethoxy-oxecane and trans-cyclohexane dicarbinol are illustrated.

                                      Table 2                                     __________________________________________________________________________    No. Monomer      Monomer         Polymer                                      __________________________________________________________________________    46                                                                                 ##STR38##                                                                                  ##STR39##                                                                                     ##STR40##                                   47                                                                                 ##STR41##                                                                                  ##STR42##                                                                                     ##STR43##                                   48                                                                                 ##STR44##                                                                                  ##STR45##                                                                                     ##STR46##                                   __________________________________________________________________________

EXAMPLE 49

The procedure of Example 45 was repeated in this example with allconditions as described except the following monomers were used:2,2-diethoxytetrahydrofuran, 50 grams (0.312 mole) and 1,10 decanediol,54.7 grams (0.312 mole) with 0.05 grams of polyphosphoric catalyst. Thepolymerization reaction is as follows: ##STR47## wherein the polymer hada Mw = 5.78×10⁴, Mn = 5.98×10³, and a Mw/Mn = 9.66.

EXAMPLE 50

The procedure of Example 45 was repeated in this example with allconditions as described except for the following:2,2-diethoxytetrahydrofuran 100.0 grams (0.625 mole); trans-cyclohexanedicarbinol 81.0 grams (0.562 mole); 1,6 hexanediol 7.38 grams (0.0625mole); and polyphosphoric acid 0.10 grams; with a polymerization time of18.5 hours. The random polymer produced had the following properties asmeasured by gel permeation chromatography calibrated with polystyrenestandard: Mw = 11,500, Mn = 3,600; Mw/Mn = 3.2. The synthesis andpolymer is as follows: ##STR48##

EXAMPLE 51

The procedure of Example 50 was followed in this example and allconditions were as previously described except, the monomers were2,2-diethoxytetrahydrofuran 100 grams (0.625 mole) and 1,6-hexanediol73.7 grams (0.625 mole). The yield was 89 g, and the polymer had a Mw =18×10³, Mn = 3.5×10³, and Mw/Mn = 5.4.

EXAMPLE 52

A mixture consisting of 140 grams (0.874 mole) of2,2-diethoxytetrahydrofuran, 124.7 grams (0.865 mole) oftrans-cyclohexane dicarbinol and 0.14 grams of polyphosphoric acid washeated to 130° C for 5 hours in an N₂ atmosphere for transesterifyingthe monomers. Then, with the temperature at 130° C, the pressure wasreduced to 0.01 mm Hg over a 2 hour period, followed by the temperaturebeing increased to 180° C, with the distillation of a viscous material,having a vapor temperature of 150° C. During the exothermic stage, heatwas applied only to the bottom of the flask. The exothermic stagesubsided after 4 hours and the heat was then applied to the whole flask.After 96 hours of reaction time, at 180° C, the polymerization wasterminated. The work-up procedure consisted of dissolving the polymer in400 ml of dry benzene, followed by filtration and lyophilization. Theyield was 159 g, with Mn = 9,000, Mw = 34,000, and Mw/Mn = 3.7. Thepolycondensation reaction is as follows: ##STR49##

EXAMPLE 53

50 grams of 2,2-diethoxytetrahydrofuran and 28.1 grams of 1,4-butanediol previously mixed with 0.05 grams of polyphosphoric acid, werereacted for 3.25 hours over an increasing temperature span of 70° to130° C, and under atmospheric pressure according to Example 45. Then thereactants were heated under reduced pressure of 120 mm to 2.4 mm Hg for4 hours at 110° to 125° C to yield 1,6,8-trioxa-spiro(4,6)undecane. Thespiro compound was polymerized in a sealed tube at 125° C in thepresence of a Lewis acid catalyst, i.e. SbF₅, PF₅ or BF₃, to yield thepolymer, where n is 10 to 1000. ##STR50##

EXAMPLE 54

The polycondensation of 2,2-diethoxytetrahydrofuran and 30/70cis/trans-cyclohexanedimethanol with polyphosphoric acid was carried outas follows: the catalysts' weight ratio to diethoxytetrahydrofuran was1/500, the monomer ratio of cyclohexanedicarbinol to tetrahydrofuran was2.2/1, and the cyclohexanedicarbinol was introduced into the reactor asa 68% weight solution in methanol. The methanol was distilled from thediol in situ, and toluene was added to azeotrope water from the system.The tetrahydrofuran was then added and transesterification andpolycondensation carried out at 180° C and at a vacuum of 24 millitorsover a 24 hour period. The recovered yield was 82%. GPC analysis was asfollows: Mw = 36,000, Mn = 8,500, Mw/Mn = 4.3. The polymer prepared bythe example was embraced by the following formula: ##STR51## wherein bis 2 to 6 and n is 10 to 1000, and it had the specific formula asfollows: ##STR52##

EXAMPLE 55

The polycondensation of 2,2-diethoxytetrahydrofuran and 30/70 cis,trans-2-methyl-1,6-cyclohexanedimethanol with the acid catalystpolyphosphoric acid was carried out using a catalyst weight ratio totetrahydrofuran of 1/500, and a monomer ratio of lower alkyl substitutedcyclohexanedicarbinol to the monomeric cyclic orthoester of 2.2/1 asfollows: first the cyclohexanedicarbinol was introduced into the reactoras a 68% weight solution in anhydrous methanol, with the methanoldistilled from the diol in situ, followed by the addition of toluene andthe catalyst to azeotrope water from the reaction system. Next,tetrahydrofuran was added and polycondensation carried out at 180° andunder a vacuum of 24 millitors over a 24 hour period to yield thepolymer having a molecular weight in excess of 35,000. The polymerprepared is represented by the general formula: ##STR53## wherein n is 0or 1, b is 2 to 6 and n is greater than 10, generally 10 to 1000 orhigher. The polymer yield was 80% and it had the following structure:##STR54##

EXAMPLES 56 - 58

The procedure set forth in Example 55 is repeated in these examples,with all reaction conditions as previously described, except thefollowing monomers are substituted for those previously set forth:

2,2-diethoxytetrahydrofuran and 5-methyl-1,6-cyclohex-Δ² -enedicarbinol;

2,2-dipropoxy-1,3-dioxolane and 2-ethenyl-1,6-cyclohexanedipropanol; and

2,2-diethoxy-5-methyl-1,3-dioxolane and3-methyl-1,5-cyclopentanediethanol, to yield the following polymers:##STR55##

EXAMPLES 59 - 66

In the instant examples, polymers are provided according to theprocedure of Example 55. The polymers are prepared by reacting a cyclicortho carbonate monomer with a polyol wherein the monomer pairs are asfollows:

2,2-dialkoxy-1,3-dioxolane and 1,6-hexamethylene diol;

2,2-dialkoxy-1,3-dioxolane and 1,4-phenylene dicarbinol;

2,2-dialkoxy-1,3-dioxane and 1,7-heptamethylene diol;

2,2-dialkoxy-1,3-dioxepane and2-methyl-cis-trans-1,6-cyclohexanedipropanol;

2,2-dialkoxy-1,3-dioxocane and 3-ethyl-1,5-cyclopentane diethanol;

2,2-dialkoxy-1,3-dioxonane and 1,6-cyclohex-2-enediethanol;

2,2-dialkoxy-1,3-dioxolane and 3-hexenylene-1,6-diol; and

2,2-dialkoxy-1,3-dioxolane and 1,6-cyclohexane dibut-2-enyl diol; toyield the corresponding polymers of the formula: ##STR56## wherein b is2 to 6, n is 10 to 1000 and the polymers are as follows:

poly(2,2-dioxohexamethylene-1,3-dioxolane);

poly(2,2-dioxo-1,4-phenyldimethylene-1,3-dioxolane);

poly(2,2-dioxo-2-methyl-cis,trans-1,6-cyclohexane-dipropylene-1,3-dioxepane);

poly(2,2-dioxo-3-ethyl-1,5-cyclopentane diethylene-1,3-dioxocane);

poly(2,2-dioxo-1,6-cyclohex-2-ene diethylene-1,3-dioxonane),

poly(2,2-dioxo-1,6-hex-3-enelene-1,3-dioxolane);

poly(2,2-dioxo-1,6-cyclohexane dibut-2-eneylene-1,3-dioxolane).

EXAMPLE 67

The polycondensation of 2,2-diethoxytetrahydrofuran with 1,6-hexanediolin the presence of p-toluene sulfonic acid catalyst with the catalysthaving a weight ratio of 1/500 to the 2,2-diethoxytetrahydrofuran andthe monomer ratio of 2.2/1 of hexanediol to diethoxytetrahydrofuran wascarried out as follows: first, the hexanediol was introduced into thereactor and mixed with freshly distilled toluene. Then, toluene wasdistilled in situ to azeotrope water from the system. Next, thediethoxytetrahydrofuran and p-toluene sulfonic acid were added andtransesterification and polycondensation carried out at 180° C and 10millitors of vacuum over a 27 hour period to yield the polymer, having aGPC analysis as follows: Mw = 92,000; Mn = 10,000; Mw/Mn = 9.2.

EXAMPLES 68 - 69

Repeating the procedures of Examples 54 and 55, copolymers andterpolymers are synthesized from polyols, orthoesters, orthocarbonatesand preformed polymers to yield polymers having the following genericformula: ##STR57## wherein a is 0 or 1; b is 2 to 6; R₁ is independentlythe same or different in each repeating polymeric unit, where R¹ is asdefined previously, and n, m, and p are 10 to 1000.

EXAMPLE 70

13.26 grams (0.125 mole) of diethylene glycol was added to 20.0 grams(0.125 mole) of 2,2-diethoxytetrahydrofuran and the monomers reacted inthe presence of a Lewis acid for 42 hours according to Examples 11 and12 to yield poly(2,2-dioxodethylene glycol tetrahydrofuran). Separately,50.0 grams (0.312 mole) of trans-1,4-cyclohexane dicarbinol and 50.0grams (0.312 mole) of 2,2-diethoxytetrahydrofuran was reacted accordingto Example 1 to yield poly(2,2-dioxo-transcyclohexane dimethylenetetrahydrofuran. Separately, 14.77 grams (0.125 mole) of 1,6-hexanediolwas added to 20.0 grams (0.125 mole) of 2,2-diethoxytetrahydrofuran and20 mg of p-toluene sulfonic acid, and the monomers reacted according toExample 1, to yield poly(2,2-dioxohexamethylene tetrahydrofuran). Then,0.51 mole of poly(2,2-dioxodiethylene glycol tetrahydrofuran), 0.51 moleof poly(2,2-dioxo-trans-cyclohexane dimethylene tetrahydrofuran) and0.51 mole of poly(2,2-dioxohexamethylene tetrahydrofuran was polymerizedfor 50 hours at 180° C under 0.01 mm Hg in the presence of trace amountsof acid catalyst to yield the terpolymer. ##STR58##

EXAMPLE 71

68.2 grams of trans-cyclohexane dicarbinol and 0.1 grams ofpolyphosphoric acid were added to 50 grams of5-methyl-2,2-diethoxytetrahydrofuran, that was previously treated withsodium to remove any traces of ethanol and the polymer polymerizedaccording to Example 1 to yield 46.2 grams of polymer. The polymer had aMn of 10,000, an Mw of 36,000, an Mw/Mn of 3.6 and a structural formulaas follows: ##STR59##

DETAILED DESCRIPTION OF APPLICATION OF THE INVENTION

The polymers of the invention are useful for making articles ofmanufacture including devices and coatings for releasing beneficialagents. The polymers can be processed into articles, including deliverydevices and coated onto an agent by standard manufacturing techniques.For example, the polymers can be extruded into filaments, spun intofibers, pressed into shaped articles, solvent film cast, doctor-bladedinto thin films, coated onto an agent by solvent evaporation, coated byusing a fluidized bed, compression and transfer molded, and processed bylike standard methods of manufacture.

The polymers of the invention can be used as a single film, in a numberof layers made of the same or of different polymers, and they can bemade into devices of various geometric shapes, for example flat, square,round, tubular, disc, ring, and the like. Also, the devices of theinvention are sized, shaped and adapted for implantation, insertion orplacement on the body, in body cavities and passageways, or forpositioning in other environments of use for example, streams,aquariums, fields or reservoirs. Standard procedures for processingpolymers are described in Plastic Encyclopedia, Vol. 46, pages 62 to 70,1969.

The polymers of the invention are useful for making devices fordispensing an active agent, as they have a controlled degree ofhydrophobicity in the environment of use and because they erode intoinnocuous products at a continuous rate which exhibits no knowndeleterious effects on the environment or towards an animal body.

The term "hydrophobicity" as used above and in the remainder of thespecification broadly refers to the property of the polymers not toabsorb appreciable amounts of water. For the purpose of the subjectinvention, the hydrophobic polymers when they do absorb water, do notabsorb it in an amount exceeding 5 percent of their dry weight.

The terms "erodible" and "bioerodible" as used herein define theproperty of the polymers to break down as a unit structure or entity ina non-biological or in a biological environment over a period of time toinnocuous products. The terms "erosion", "bioerode" and "bioerosion"generally define the method and environment where breakdown ordegradation of the polymer occurs.

The phrase "prolonged period of time" as used herein, generally meansthe period between the start of erosion or the breakdown of the polymerswhen the polymers are placed in a moisture laden environment and thatperiod in time when the polymer is gone. Depending upon the structureand dimensions of the device, such as number of layers and thickness,the period may continue over days, several months such as ninety days,one hundred and eighty days, a year or longer. The environment includesaqueous and aqueous-like biological environments.

The polymers are, as previously noted, useful for making devices forreleasing a wide variety of active agents. The term "agent" as used inthe specification and accompanying claims includes any compound, mixtureof compounds, composition of matter consisting of a compound and acarrier, which when released from a device produces a beneficial anduseful result. The term "active agent" includes pesticides, herbicides,germicides, biocides, algicides, rodenticides, fungicides, insecticides,plant growth promoters, plant growth inhibitors, preservatives,disinfectants, sterilization agents, cosmetics, drugs, plant foods,vitamins, sex sterilants, plant hormones, fertility inhibitors,fertility promoters, air purifiers, micro-organism attenuators, andnutrients.

The term "drug" as comprehended by active agent, broadly includesphysiologically or pharmacologically active substances for producing alocalized or systemic effect or effects in mammals including humans andprimates, avians, valuable domestic household, sport or farm animalssuch as sheep, goats, cattle, horses, etc., or for administering tolaboratory animals such as mice, rats and guinea pigs. That is, thedevice of the invention can be used for administering drugs that areactive at a point in near relation to the delivery device, or, foradministering drugs which will produce a response at a site remote fromthe point of application of the drug delivery device. The drugs that maybe administered include inorganic and organic drugs without limitation,are those drugs that can be transported across a vessel, for example,drugs acting on the central nervous system such as hypnotics andsedatives, mixtures thereof such as pentobarbital sodium, phenobarbital,secobarbital, thiopental, etc.; heterocyclic hypnotics such asdioxopiperidines, and glutarimides; hypnotics and sedatives such asamides and ureas exemplified by diethylisovaleramide andα-bromo-isovaleryl urea; and hypnotic and sedative urethanes anddisulfanes; narcotic antagonists such as naloxone and cyclazocine;psychic energizers such as isocarboxazid, nialamide, phenelzine,imipramine, tranylcypromine and paraglyene; tranquilizers such aschloropromazine, promazine, fluphenazine, reserpine, deserpidine;meprobamate and benzodiazepines such as chlordiazepoxide;anticonvulsants such as primidone, diphenylhydantoin, ethltoin,phenetruide and ethosuximide; muscle relaxants and antiparkinson agentssuch as mephenesin, methocarbomal, trihexylphenidyl, biperiden andlevo-dopa, also known as L-dopa and L-β-3-4-dihydroxyphenylalanine;analgesics such as morphine, codeine, meperidine and nalorphine;antipyretics and anti-inflammatory agents such as aspirin, salicylamideand sodium salicylamide; local anesthestics such as procaine, lidocaine,naepaine, piperocaine, tetracaine, and dibucane; antispasmodics andantiulcer agents such as atropine, scopolamine, methscopolamine,oxyphenonium, papaverine and prostaglandins such as PGE₁, PGE₂, PGF₁α,PGF₂α, and PGA; anti-microbials such as penicillin, tetracycline,oxytetracycline, chlorotetracycline, and chloramphenicol; sulfonamides;anti-malarials such as 4-aminoquinolines, 8-aminoquinolines andpyrimethamine; antivirals including idoxuridine, hormonal agents such asprednisolone, cortisone, cortisol and triamcinolone; androgenicsteroids, for example methyltestosterone and fluoxmesterone; estrogenicsteroids, for example, 17β-estradiol and ethinyl estradiol;progestational steroids, for example, 17α-hydroxyprogesterone acetate,19-nor-progesterone, norethindrone and progesterone; sympathomimeticdrugs such as epinephrine, amphetamine, ephedrine, and norpinephrine;cardiovascular drugs, for example, procainamide, amyl nitrite,nitroglycerin, dipyridamole, sodium nitrate, and mannitol nitrate;diuretics, for example, chlorothiazide, and flumethiazide; antiparasiticagents such as bephenium hydroxynaphthoate, dichlorophen, dapsone andenitabas; neoplastic agents such as mechlorethamine, uracil mustard,5-fluorouracil, 6-thioquaniine, and procarbazine; hypoglycemic drugssuch as insulin, isophane insulin suspension, protamine zinc insulinsuspension, globin zinc insulin, extended insulin zinc suspension, andother like insulins derived from animal and synthetic origin includingtolbutamide, acetohexamide, tolazamide, and chloropropamide; nutritionalagents, for example vitamins such as ascorbic acid, essential aminoacids, essential elements such as iron, and essential fats; ophthalmicdrugs such as pilocarpine base, pilocarpine hydrochloride, pilocarpinenitrate, eserine salicylate, atropine sulfate, homatropine, andeucatropine. The above drugs are further described in ThePharmacological Basis of Therapeutics, Edited by Goodman and Gilman, 4thEdition, 1970, published by The Macmillan Company.

The agents or drugs also can be in various forms, such as unchargedmolecules, components of molecular complexes, pharmacologicallyacceptable salts such as hydrochloride, hydrobromide, sulfate, laurates,palmatates phosphate, nitrate, borate, acetate, maleate, tartrate,oleates, and salicylates. For acidic drugs, salts of metals, amines, ororganic cations, for example quaternary ammonium can be employed.Furthermore, simple derivatives of drug such as esters, ethers, andamides which have solubility characteristics that are suitable for thepurpose of the invention. Also, an agent or drug that is water insolublecan be used in a form that is a water soluble derivative thereof toeffectively serve as a solute, and on its release from the device, it isconverted by enzymes, hydrolyzed by body pH, or metabolic processes tothe original form or to a biologically active form. Additionally, agentor drug formulation within the devices can have various art known formssuch as solution, dispersion, paste, cream, particle, granule,emulsions, suspensions and powders.

Representative of other active agents suitable for use with the devicesof this invention include without limitation, insecticides applied toimmature insects, namely during the embryo, larvae or pupae stage aseffecting metamorphosis and leading to abnormal development, death orthe inability to reproduce. These include aliphatic α β-unsaturatedesters having a lower alkoxy groups which are effective for Hemipteransuch as Lygaeidae, Miridae and Pyrrhocoridae; Lepidropteran such asPyralidae, Noctuidae and Gelechiidae; Coleopteran such as Tenebrionidae,Crysomelidae and Dermestidae; the Dipteran mosquitos and flies;Homopteran such as asphids and other insects. The compounds aredelivered at dosage levels of the order of 0.01 micrograms to 25.0micrograms per insect.

Additional representative agents include cyclopentane insecticides ofthe formula: ##STR60## wherein R₆, R₇, R₁₀, R₈ and R₉ are selected fromthe group consisting of lower alkyl and R₅ is a member selected from thegroup consisting of methyl and ethyl, for use against Lepidoptera,Diptera and Coleoptera. The device can also be used to deliver juvenilehormones such asmethyl-10,11-(cis)osido-7-ethyl-3,11-dimethyltrideca-2(trans),6(trans)-dienoate andmethyl-10,11(cis)oxido-3,7,11-trimethyltrideca-2(trans),6(trans)-dienoate. Other agents which can be delivered include2,3,5-trichloropyridine-4-ol; 4-(methylthio)-3,5-xylyl N-methylcarbamate; O-isopropoxyphenyl N-methyl carbamate; O,O-dimethylS(N-methylcarbamoyl) methyl phosphorodithioate; and2,4-dichlorophenoxyacetic acid.

The polymers prepared according to the invention, are useful for coatingnumerous agents such as for providing slow release fertilizers. Thefertilizers are coated in their conventional form such as granules,powder and beads. Fertilizers that can be coated include the urea,fertilizers with slow ammonia release, fertilizers in the form of saltssuch as elements of carbon, nitrogen, phosphorus, sulfur, potassium,calcium, magnesium, manganese, zinc, copper and boron and the like.Additionally, the fertilizer can be impregnated into, or suitablyadmixed with inert materials such as silica and coke.

The polymers, in view of the stated properties, are especially useful asbioerodible, agent-release, rate controlling materials as they bioerodeat a controlled and continuous rate concurrently with the release ofagent at a corresponding controlled and continuous rate. Devices madewith the present polymers are reliable and easy to use for releasing anagent as they normally require intervention or handling only at the timewhen the device is positioned in the environment of use or the animal.Additionally, the devices can be made to release an agent at a zeroorder rate or at a variable rate by controlling the molecular weight andcomposition of the polymer, by controlling the concentration of theagent in the polymer and the surface area exposed, and by making thedevices with different polymers that undergo bioerosion and agentrelease at different rates. Examples of devices made available to theart by the invention are described below the devices in the figures andspecification are for administering an active agent, mainly a drug, andthese devices are set forth to illustrate various embodiments of theinvention. That is, they are not to be construed as limiting as otherdevices will be apparent to those versed in the art from thespecification, the drawings and the accompanying claims. Also, thedevices in the drawings are not necessarily drawn to scale and likeparts in related figures are identified by like numbers.

In FIG. 3, a device 10 prepared by using a polymer of the invention, isseen comprising a wall 11 forming a matrix made of bioerodible polymer12 having an agent 13, a drug in this embodiment, dispersed therein.Device 10 can be used for the continuous administration of a locallyactive drug to an organ, mucosa, derma, or to any local drug receptor,or device 10 can be used for administering a systemically active drugfor transport from the place of administration by the circulatory systemto produce a physiologic or pharmacologic response at a distant site. Inone embodiment, device 10 is square shaped having dimensions of 3 in. ×3 in. × 10 mil, and it was made by mixing intopoly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran)hydrocortisone as follows: 2.375 grams of the polymer was heated in alaboratory, Teflon® flat coated pan equipped with a surface thermometerto about 150° C, and then 0.125 grams of micronized hydrocortisone wasadded to the polymer. Next, the polymer and hydrocortisone werethoroughly mixed to produce a good dispersion of the drug, and to yielda 5% hydrocortisone loaded polymer. After the pan cooled to roomtemperature, the polymer drug formulation was removed from the pan andsolid film prepared by pressing the polymer at 250° F (121.1° C), and at10,000 psi for 5 minutes with a 10 mil, 3 in. × 3 in. spacer, positionedbetween Teflon® sheets. The devices were prepared under an essentiallydry, inert atmosphere using oven dried apparatus. Device 10 surfacebioerodes in an aqueous environment at a controlled and continuous rateof about two microns of depth per hour. Concurrently, hydrocortisone isreleased at a like controlled and continuous, but proportional rate.Device 10 can be used for the management of inflammation, and bursitiswhen applied to a drug receptor site.

In FIG. 4, a device 10 is seen for administering an agent 13 at variablerates over a period of time. Device 10 is a multilayered structurecomprised of two outer layers 14 and 16, distant from each other with alayer 15 positioned between layers 14 and 16. All the layers can be madeof different bioerodible polymers, or layers 14 and 16 can be made ofthe same polymer with layer 15 made of a different polymer. An agent 13is dispersed in each layer and it can be the same or different in thelayers. In operation, when outer layer 14 has bioeroded at a controlledand continuous rate to release agent 13, middle layer 15 is exposed andreleases its agent at a rate corresponding to the bioerosion rate of thepolymer. When layer 15 has bioeroded away, layer 16 is exposed andbegins to bioerode and release its agent over a period of time. Manyvariations of device 10 of FIG. 4 will be apparent to those skilled inthe art of dispensing, especially drug delivery. For example, a greaternumber of layers can be used, a variety of agents including drugs, canbe used in the several layers, and polymers having different bioerosionrates can be used for obtaining different delivery patterns.

In one embodiment, device 10 of FIG. 4 is designed for releasing a drugand it is made by using as its outer layers 14 and 16, the polymer drugformulation used in FIG. 3, with layer 15 made of a different polymerdrug formulation. Layer 15 has the same dimensions as layers 14 and 16and it is made by mixing into 2.375 grams ofpoly(2,2dioxotrans-1,4-cyclohexane dimethylene-5-tetrahydrofuran) 0.125grams of micronized hydrocortisone and processing the polymer drugmixture as described in FIG. 3. Then, the three layers are pressedtogether to give the device of FIG. 4.

FIG. 5 illustrates another device 10 made by using the bioerodiblepolymers of the invention. Device 10 is a means for delivering an agent13 including a drug, that is difficult to disperse within the subjectpolymers. Device 10 consists of two layers 14 and 15, each formed of adifferent polymer having a different bioerosion rate. Layer 14 consistsof a polymeric matrix containing a plurality of cells 17 dispersedthroughout the matrix. An agent 13 is present in cells 17, which agentis dissolved in a liquid 18 that is a solvent for the agent and anonsolvent for the polymer. Layer 15 can have the same thickness or adifferent thickness as layer 14, and it contains particles of adifferent agent 13 dispersed therein. When device 10 is placed in theenvironment of use, for example against an animal organ, or in a bodycavity, layer 14 gradually bioerodes and releases dissolved agent 13 tothe surrounding tissues. After layer 14 has disappeared, bioerosionproceeds to layer 15 with layer 15 bioeroding and releasing dispersedagent 13 to surrounding tissue. Many variations of device 10 will beapparent to those skilled in the art. For example, a greater number oflayers can be used, a variety of agents, including drug, dosage formscan be employed in the layers, and different polymers having differentbioerosion rates can be used in different layers. Device 10 can be madeby known prior art techniques which form closed cells and entrapliquids. One such technique suitable for the present purpose is thesolvent precipitation technique. This technique consists in using atleast two miscible liquids with at least one of the liquids anon-solvent for the polymer and having a lower volatility than the otherliquids. In preparing a device, first the polymer and the liquids aremixed to form a single phase. Next, the liquids, which have highervolatilities than the non-solvent, are removed by evaporation to form afilm containing a plurality of discrete closed cells having entrappedtherein droplets of non-solvent, which is the liquid in the cells. Theliquid serves as a carrier for beneficial agents, for example medicines,deodorants, fungicides and disinfectants.

FIG. 6 illustrates a device 10 formed of a bioerodible polymer 12comprising a multiplicity of microcapsules 19 with each microcapsulehaving a wall 20 made of an agent release rate controlling material. Anagent 13 is housed within microcapsules 19. Device 10 can bemanufactured with different designs, for example in one embodiment,microcapsules 19 are present in polymer 12 in clusters, while in anotherembodiment, microcapsules 19 are uniformly distributed throughoutpolymer 12. Device 10, when placed in the environment of use, bioerodesat a controlled and continuous rate releasing microcapsules 19 to thesurrounding tissues which then dispense agent 13 by passage throughrelease rate controlling wall 20. The microcapsules used herein can bemade by standard coacervation methods. The coacervation method consistsessentially of the formation of three immiscible phases, a liquidmanufacturing phase, a core phase and a coating phase with deposition ofthe liquid polymer coating on the core material and rigidizing thecoating, usually by thermal, cross-linking or desolvation techniques toform microcapsules. The microcapsules made by the above technique havean average size of from several tenths of a micron to 5,000 microns,although this feature is not critical to the practice of the invention.Techniques for preparing microcapsules, such as the classic Bungenbergde Jong and Kass method are reported in Biochem. Z., Vol. 232, pages 338to 345, 1931; Colloid Science, Vol. 11, "Reversible System", edited byH. R. Kruyt, 1949, Elsevier Publishing Company, Inc., New York; J.Pharm. Sci., Vol. 59, No. 10, pages 1367 to 1376, 1970; Remington'sPharmaceutical Science, Vol. XIV, pages 1676 to 1677, 1970, MackPublishing Company, Easton, Pennsylvania; and in German Pat. No.1,939,066.

In FIG. 7, a device of aid in the healing of injuries is showncomprising a support base layer 21 formed of a breathable imperviousmaterial such as cellophane, rubber or polyethylene and the like, with abioerodible solid polymer 12 containing agent 13, a drug, fixed to base21. A protective facing material 22, such as coated paper, plastic filmor crinoline is adapted to overlay polymer 12, and it is removed priorto application of device 10. Device 10 is useful for administering drug13 to the skin, mucosa or an exposed wound simply by applying the devicefor the controlled release of drug as polymer 12 bioerodes. After thetherapeutic program is completed, device 10 is removed and discarded.

In another embodiment, not shown, device 10 is an ointment consisting ofa polymer 12 and a drug 13 and it was prepared as follows: to 2.375grams of the viscous polymer poly(2,2-dioxo-1,6-hexamethylenetetrahydrofuran), having a molecular weight of about 25,000, was added0.125 grams of 11β,17,21 -trihydroxypregn-4-ene-3,20-dione and theingredients thoroughly mixed for 5 minutes to yield device 10. Themixing was done with standard laboratory blending equipment, at roomtemperature, and in a dry, inert atmosphere. Device 10 is useful for thecontrolled and continuous release of drug 13 when applied to theenvironment of use by inunction.

FIG. 8 depicts a pharmaceutical device particularly adapted for use as adepot implant. Depot implant 10 is manufactured for administering a drug13 and it is comprised of a pair of layers 14 and 16 having sandwichedtherebetween a single layer 15. Layers 14 and 16 are made from the sameor different biodegradable polymers and they have the same or differentdrug incorporated therein. Layer 15 is made from a different polymerhaving a different bioerosion rate than layers 14 and 16, whileoptionally, it can contain the same or a different drug. Drug deliveryis accomplished by placing implant within the animal body, therebyadministering drug at a controlled and continuous rate over a prolongedperiod of time. One advantageous use of the implant is in surgicaloperations accompanied by severe pain after the operation is completedand the patient regains consciousness. In these cases, when the body isopened for the operation, an implant containing an analgesic can beimplanted into the body during the operation to ease pain as itbioerodes and releases the analgesic drug throughout the recoveryperiod.

In addition to the surgical implants 10 as just described, the inventionalso provides injectable implants made of the novel polymers 12 of theinvention. These implants are useful for releasing drugs 13 over aprolonged period of time at various rates for example 200, 600 or 1200μg per day. An injectable implant comprising a polymer having an erosionrate of about 2 microns per hour in a biological aqueous environmentwith a physiological pH of 6 to 8 and a drug concentration of 5% wasprepared as follows: To 2.375 g of poly(2,2-dioxo-trans-1,4-cyclohexanedimethylene tetrahydrofuran) was added 0.125 g of hydrocortisone and theingredients heated to 150° C to give a melt. The drug was dispersedthroughout the melt by mixing the ingredients for 5 minutes to give agood dispersion. The mixing was performed in a dry, inert environment,at atmospheric pressure, and with dry equipment. Next, after the polymercooled to room temperature, it was transferred to a press and injectionmolded into a solid, cylindrical shaped implant, 3 mm in diameter by 8mm long. The implant was positioned in a muscle of an animal by trocharinjection where it bioeroded and released steroid for the management ofinflammation.

A similar implant containing 20% progesterone inpoly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran) havingan original weight of about 114 mg, had an in vivo release rate ofprogesterone, expressed in mg per day over a 7 day period, as follows:3.7; 3.2; 2.9; 2.2; 2.5; and 3.8 mg respectively.

Another injectable implant containing norethisterone was prepared bydispensing the drug in poly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran) according to the procedure set forth above, except thatdrug and polymer were blended at 130° C in a dry helium atmosphere. Theimplant formed had a drug concentration of 20% and a cylindrical shape.The implant was placed bilaterally in the paravertebral muscles ofrabbits by trochar injection where it bioeroded at a controlled andcontinuous rate concomitantly with the release of norethisterone at arate of 600 μ g per day.

FIGS. 9 and 10 illustrate devices for delivering drug, which deviceshave several variables that may be manipulated to control the rate andperiod of drug release. Referring first to FIG. 9, there is illustrateda device 10 having a cylindrical shape and a passageway 20 extendedthrough the center of device 10 in parallel alignment to the cylindricalaxis of device 10. Device 10 is made of a bioerodible polymer 12 forreleasing drug within a vagina. Passageway 20 is a means formanipulating the amount of drug released from device 10 by increasingthe surface exposed to the fluid of the environment of use therebyinfluencing the amount of drug released over bioerodible time. FIG. 10illustrates another means for manipulating the rate and period of drugrelease from a device 10, and it provides the medical profession with adevice for insertion into the natural cavities of the animal body 24,such as the anus 25, where it releases a drug for promoting healingeffects. Device 10, as seen in FIG. 10, is made of two fibers 26a and26b, with one fiber 26a intertwisted with fiber 26b to provide a dualelement device 10. Fibers 26a and 26b are made of the like or unlikebioerodible polymers 12 containing the same or different drugs, therebyproviding means for influencing drug release throughout the drug releaseperiod by varying the polymer and the drug.

Referring to FIGS. 11a and 11b, a device 10 is shown for placement in ahuman eye comprising an eyeball 27 having an upper eyelid 28 and a lowereyelid 29, respectively, with the eyeball 27 covered for the greaterpart of its area by the sclera 30 and at its central portion, by thecornea 31. The eyelids 28 and 29 are lined with an epithelial membraneor palpebral conjunctiva. The sclera 30 is lined with the bulbarconjunctiva which covers the exposed portion of eyeball 27. The cornea31 is covered with an epithelial layer which is transparent. Thatportion of the palpebral conjunctiva which lines the upper eyelid 28 andthe underlying portion of the bulbar conjunctiva defines the upper sac32 and that portion of the palpebral conjunctiva which lines the lowereyelid 29 and the underlying portion of the bulbar conjunctiva definesthe lower sac 33. Upper and lower eyelashes are indicated as 34 and 35respectively.

A bioerodible ocular insert 10 made in accordance with this invention,is shown in broken lines in operative position in the lower sac 33 ofthe eye. Ocular insert 10 consists of a bioerodible polymer 12comprising a continuous matrix having particles of drug dispersedtherethrough. When ocular insert 10 is placed in the environment of theeye, polymer 12 gradually bioerodes and releases drug to the eye andsurrounding tissue.

The ocular insert 10 as illustrated in FIGS. 11a and 11b can befabricated in any convenient shape for comfortable retention in theupper sac or lower sac of the eye. The marginal outline of insert 10 canbe ellipsoid, donut-shaped, bean-shaped, banana-shaped, circular,square, rectangular, etc. In cross-section, insert 10 can be doublyconvex, concavo-convex, rectangular, and the like. Dimensions of theinsert can vary widely. The lower limit on the size of the device isgoverned by the amount of the particular drug to be supplied to the eyeand surrounding tissues to elicit the desired pharmacologic response, aswell as by the smallest sized device which conveniently can be insertedin the eye. The upper limit on the size of the device is governed by thegeometric space limitations in the eye, consistent with comfortableretention of the ocular insert. Satisfactory results can be obtainedwith an ocular device for insertion in the sac of the eye of from 4 to20 millimeters in length, 1 to 12 millimeters in width, and 0.1 to 2millimeters in thickness. Exemplary shapes of inserts include an 8 mmdisc, and a 6 mm by 12 mm ellipsoid, each punched out of a 0.4 mm thickdrug-containing polymer sheet. The drug-containing polymer sheet wasprepared by dissolving both the drug and the polymer in a dry solvent,benzene or 1,4-dioxane and the mixture lyophilized; then the dry mixturewas pressed at 100° C and 15,000 psi to give the drug-containing polymersheet. Ocular inserts prepared by this procedure include 10% pilocarpinenitrate and poly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran); 5% pilocarpine free base andpoly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydroduran); 10%hydrocortisone alcohol and poly(2,2-dioxo-trans-1,4-cyclohexanedimethylene tetrahydrofuran); 10% idoxuridine andpoly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran-2,2-dioxo-oxadimethylene-tetrahydrofuran); and 10%chloramphenicol and poly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran-2,2-dioxo-oxadimethylene-tetrahydrofuran). These ocularinserts continuously bioerode and dispense a metered amount ofophthalmic drug or a combination of drug to the eye and its surroundingtissue over a period of time.

Additional ocular devices comprising zinc bacitracin and the randomcopolymer poly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran-2,2-dioxo-1,6-hexamethylene tetrahydrofuran) wereprepared by mixing and dispersing at 120° C for 5 minutes the bacitracininto the hot melt of the polymer. After cooling to room temperature, thedrug polymer formulation was pressed into a film at 120° C under 10,000psi for 5 minutes; and then it was templated into ocular devices. Therelease rate for 3 day ocular devices made from the above drug-polymerformulation is set forth in Table 3 below:

                  Table 3                                                         ______________________________________                                        Dimension and                                                                              Surface area                                                                             Zn bacitracin                                                                            μg/hr for                                 Shape      (cm.sup.2) content (mg)                                                                             72 hrs                                     ______________________________________                                        6 mm circular                                                                              0.56       1.5        21                                         5 × 8 mm ellipse                                                                     0.62       1.6        22                                         5.6 × 12.7 mm ellipse                                                                1.1        2.9        40                                         ______________________________________                                    

In FIG. 12, there is graphically illustrated a device 10 for releasing adrug 13 within a uterus 36 having sides 37 and a fundus uteri 38. Device10 as shown in cross-section, is a bioerodible intrauterine devicehaving a round tube shaped body made of bioerodible polymer 12 thatcontains drug 13 for release in uterus 36 concurrently with thebioerosion of polymer 12. Intrauterine device 10 can have differentshapes and dimensions, and these can vary consistent with comfortableplacement and effective drug release, in uterus 36. In one application,device 10 is useful for releasing an active agent to the uterus bycontrolled bioerosion in situ. Device 10 can deliver drugs for inducinguterine contractions for example, oxytocin, ergot alkaloids such asergonovine and methylergonomine, quinine, quinidine, histamine andsparteine; and the prostaglandins; especially, PGE and PGF₂α.

The polymers prepared according to the invention are used for coatingbeneficial agents by known techniques. In one embodiment, slow releasefertilizers are made by coating fertilizers in conventional forms suchas granules, powders and beads with one of the degradable polymers ofthe invention. For example, a coated fertilizer is prepared by mixingthe polymer and the fertilizer in granular form in a fluidized bedhaving a conical bottom until an acceptable coat is applied to thefertilizer. The bed is equipped with an air inlet at the top for mixingthe polymer and fertilizer until the fertilizer is coated with 1 to 10%by weight of polymer. The temperature of the air is dependent on theconcentration of the dispersion, usually 20° to 125° C. In anotherembodiment, the fertilizer is coated by mixing the polymer with anorganic solvent to facilitate its application onto the fertilizer. Forexample, a slow release urea-based fertilizer is prepared by dissolvingthe polymer poly(1,4-cyclohexane dicarbinyl-2,2-dioxytetrahydrofuran) inbenzene and mixing therein the granules. Next, the solvent is evaporatedto yield the coated, slow release fertilizer. The coating compositioncan additionally contain pigments, dyes, driers and stabilizers. Thepolymers of the invention also can be used for coating medicines forentering the digestive tract wherein the therapeutic value of themedicine is obtained.

It will be appreciated by those versed in the art, the present inventionmakes available novel polymers useful for making items of science andcommerce including devices for dispensing a beneficial agent. Also, itwill be understood by those knowledgeable in the art, that manyembodiments of this invention can be made without departing from thespirit and scope of the invention, and the invention is not to beconstrued as limited, as it embraces all equivalents inherent therein.

We claim:
 1. A drug delivery device for the controlled and continuousadministration of drug, wherein the device comprises: (a) a shapedmatrix sized and adapted for administering drug to an animal and formedof a bioerodible drug release rate controlling pharmaceuticallyacceptable material, which material comprises a polymer of the formula:##STR61## wherein R₁ is a member selected from the group of divalent,trivalent and tetravalent radicals consisting of alkylene of 1 to 10carbons; alkenylene of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons;cycloalkylene of 3 to 7 carbons; cycloalkylene of 3 to 7 carbonssubstituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons,an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;cycloalkenylene of 4 to 7 carbons; cycloalkenylene of 4 to 7 carbonssubstituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7carbons; arylene; and arylene substituted with an alkyl of 1 to 7carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7carbons; alkenyl of 2 to 7 carbons; alkoxy of 1 to 7 carbons; alkenyloxyof 2 to 7 carbons; alkylene of 2 to 6 carbons; alkenylene of 3 to 6carbons; alkyleneoxy of 2 to 6 carbons; alkenyleneoxy of 3 to 6 carbons;aryloxy; aralkyleneoxy of 8 to 12 carbons; aralkenyleneoxy of 8 to 12carbons; oxa; OR₁ O with R₁ as defined above; a heterocyclic ring of 5to 8 carbon and oxygen atoms formed when R₂ and R₃ are taken together; aheterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with analkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2to 7 carbons formed when R₂ and R₃ are taken together; a fusedpolycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃are taken together; a fused polycyclic ring of 8 to 12 carbon and oxygenatoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7carbons and an alkenyl of 2 to 7 carbons; and wherein at least one ofsaid R₂ and R₃ is a member selected from the group consisting of alkoxy,alkenyloxy and OR₁ O; R₂ and R₃ when taken together are a memberselected from the group of heterocyclic and fused polycyclic ringshaving at least one oxygen atom in the ring; and wherein n is greaterthan 10; (b) a drug selected from the group consisting of locally andsystemically acting pharmaceutically acceptable drugs present in thematrix; and, (c) wherein the device when in operation bioerodes at acontrolled and continuous rate over a prolonged period of time, therebyadministering a therapeutically effective amount of drug to the animalat a controlled and continuous rate over a prolonged period of time. 2.The drug delivery device for the administration of drug according toclaim 1 wherein a layer formed of a drug impervious material is suitablyfixed to the matrix.
 3. The drug delivery device for the administrationof drug according to claim 1 wherein the matrix has a passageway forincreasing the surface releasing drug from the device over a prolongedperiod of time.
 4. The drug delivery device for the administration ofdrug according to claim 1 wherein the matrix comprises intertwistedfibers thereby providing means for influencing the rate of drug releasethroughout the drug release period.
 5. The drug delivery device for theadministration of drug according to claim 1 wherein the device comprisesa continuous matrix having drug dispersed therethrough and wherein thematrix has a geometric shape sized and adapted for placement on theanimal and implantation and insertion in the animal.
 6. The drugdelivery device for the administration of drug according to claim 1wherein the matrix is a wall forming a tube-shaped body containing drugtherein which drug is released by controlled bioerosion over a prolongedperiod of time.
 7. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drug inthe vagina.
 8. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for use as an implant.9. The drug delivery device for administering drug at a controlled rateover a prolonged period of time according to claim 1 wherein the deviceis sized, shaped and adapted for releasing drug in the gastrointestinaltract.
 10. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drug inthe anus.
 11. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drug inthe uterus.
 12. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drugintramuscularly.
 13. The drug delivery device for administering drug ata controlled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drugsubcutaneously.
 14. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized, shaped and adapted for releasing drug inthe eye.
 15. The drug delivery device for administering drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is manufactured as an ocular insert sized, shaped andadapted for placement in the eye, with the insert formed of drug releaserate controlling material containing drug, and which material has a drugimpervious layer on a surface thereof.
 16. The drug delivery device foradministering drug at a controlled rate over a prolonged period of timeaccording to claim 1 wherein the device is sized, shaped and adapted forreleasing drug to the skin.
 17. The drug delivery device foradministering drug at a controlled rate over a prolonged period of timeaccording to claim 1 wherein the drug is a member selected from thegroup consisting of androgenic, estrogenic, and progestational steroids.18. The drug delivery device for administering drug at a controlled rateover a prolonged period of time according to claim 1 wherein the drug isa member selected from the group consisting of 17α-hydroxyprogesterone,19-nor-progesterone, progesterone and norethindrone.
 19. The drugdelivery device for administering an effective amount of drug at acontrolled rate over a prolonged period of time according to claim 1wherein the device is sized and shaped as an implant formed ofpoly(2,2-dioxo-cis/trans-1,4-cyclohexane dimethylene tetrahydrofuran)containing norethindrone.
 20. The drug delivery device for administeringdrug at a controlled rate over a prolonged period of time according toclaim 1 wherein the device is sized and shaped as an implant adapted foradministering drug to a human, and wherein the implant is formed ofpoly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran) andthe drug is hormonal 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one usefulas a fertility inhibitor.
 21. The drug delivery device for theadministration of drug according to claim 1 wherein R₁ is divalent, R₂and R₃ are taken together to form a heterocyclic ring with R₂ a memberselected from the group consisting of alkyleneoxy and alkenyleneoxy, andR₃ is a member selected from the group consisting of alkyleneoxy,alkenyleneoxy and alkylene.
 22. The drug delivery device foradministering drug at a controlled rate over a prolonged period of timewherein the locally and systemically acting drug according to claim 1 isa member selected from the group consisting of physiologically andpharmacologically effective central nervous system drugs, hypnotic,sedative, psychic energizer, tranquilizer, anticonvulsant,antiparkinson, muscle relaxant, analgesic, antipyretic,anti-inflammatory, anesthetic, antispasmodic, antimicrobial, antiviral,antiulcer, hormonal, sympathomimetic, diuretic, hypoglycemic, vitaminand opthalmic drug which drug is released in a therapeutically effectiveamount as the device bioerodes over a prolonged period of time.
 23. Thedrug delivery device for the administration of an antimicrobial drugaccording to claim 1 wherein the device is formed ofpoly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and wherein the deviceis adapted for application to the skin by inunction.
 24. The drugdelivery device for administering drug according to claim 1 wherein thematrix and drug form an ointment for topical application to skin, mucosaand wounds, and wherein the polymer is viscouspoly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and the drug issulfonamide.
 25. The drug delivery device for administering drugaccording to claim 1 wherein the device is adapted for application toskin, mucosa and wounds, and wherein the device comprises an ointmentand a support layer with the layer made of a non-toxic material, andwherein the ointment is formed of matrix and drug, which matrix isviscous poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and which drugis sulfonamide.
 26. A drug delivery device for the controlledadministration of drug, wherein the device comprises: (a) a shapedmatrix sized and adapted for administering drug to a human and formed ofa hydrophobic, bioerodible drug release rate controlling material, whichmaterial comprises a polymer of the formula: ##STR62## wherein R₁ is amember selected from the group consisting of alkylene of 1 to 10carbons; alkenylene of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons;cycloakylene of 3 to 7 carbons; cycloalkylene of 3 to 7 carbonssubstituted with a member selected from the group consisting of an alkylof 1 to 7 carbons, an alkoxy of 1 to 7 carbons, alkylene of 1 to 10carbons, and an alkenyl of 2 to 7 carbons, cycloalkenylene of 4 to 7carbons, cycloalkenylene of 4 to 7 carbons substituted with an alkyl of1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7carbons; arylene; and arylene substituted with an alkyl of 1 to 7carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons;and wherein a is 0 or 1, b is 2 to 6, and n is greater than 10; (b) adrug selected from the group consisting of physiologically andpharmacologically active drugs present in the matrix; and (c) whereinthe device when in operation bioerodes and releases drug at a ratepreselected from (1) a zero order rate, (2) a continuous rate and (c) avariable rate, which rate is produced by preselecting the polymer, thedrug and the geometric shape of the device.
 27. A drug delivery devicefor the controlled and continuous administration of drug according toclaim 1, wherein the matrix is poly(2,2-dioxo-cis/trans-1,4-cyclohexanedimethylene tetrahydrofuran).
 28. A drug delivery device for thecontrolled and continuous administration of drug according to claim 1,wherein the matrix is poly(2,2-dioxo-trans-1,4-cyclohexane dimethylenetetrahydrofuran).
 29. A method for the controlled administration of adrug to an animal which method comprises administering the drug deliverydevice according to claim 1 to the animal.
 30. A method for thecontrolled administration of a drug to an animal which method comprisesadministering the drug delivery device according to claim 1, wherein theanimal is a mammal, the device is sized, shaped and adapted forimplantation in the mammal, and the drug in the device is a memberselected from the group consisting of estrogenic and progestationalsteroids.
 31. The method for the controlled administration of drugaccording to claim 29, wherein the animal is a human.